John L. Marshall, MD: Paul, talk a little bit about BRAF-mutant tumors. These are tumors that we think of as bad and tend to have a worse prognosis. Do we give EGFR therapies or not? Recent studies are trying to address this. Dr. Scott Kopetz’ SWOG S1406 study—talk a little bit about that.

Paul R. Helft, MD:BRAF-mutant tumors are sort of our arch enemy, in a way. They only account for about 8% or 9% of total colorectal cancers, but they’re obviously a driver mutation. They drive a really terrible biology because they tend to have a much worse prognosis. And, in a predictive sense, it is a negative predictive marker of response to therapy. They tend to not respond well to therapy.

Dr. Scott Kopetz of The MD Anderson Cancer Center, who’s a really terrific young clinician, investigator, and scientist, led SWOG S1406, which was a trial in patients who have BRAF mutations of irinotecan plus cetuximab with or without vemurafenib. Playing on this interest in whether or not we can inhibit the effects of the BRAF mutation in this population—because, clearly, as a single agent, this is not working at all in colorectal cancer, so hence the combination—there was indeed, in this abstract, a 2.5-month progression-free survival advantage. And, if the patients had not seen irinotecan, previously, there was almost a 6-month progression-free survival advantage in that trial.

John L. Marshall, MD: But the control arm of BRAF-mutated tumors with EGFR make it look like it did the work. So, for me, at least, this is practice changing because I don’t really want to give an EGFR therapy to a BRAF-mutated tumor without this combination. Do you agree?

Fortunato Ciardiello, MD, PhD: I agree.

John L. Marshall, MD: How do we get it? Is this one of those situations where you call up the company and ask for approval?

Paul R. Helft, MD: Or, I think, use the trial as a mechanism for getting United States insurance companies…

John L. Marshall, MD: The upcoming trial, the BEACON CRC study, I think?

Tanios Bekaii-Saab, MD: The BEACON CRC study, yes.

John L. Marshall, MD: But, that has a control arm, right?

Tanios Bekaii-Saab, MD: It has a control arm with FOLFIRI (folinic acid, fluorouracil, and irinotecan)/cetuximab. Unfortunately, you have to have that arm. But, like you said, at least in the United States, these agents are available. For patients where I didn’t have a trial, I’ve actually been able to get them. You wouldn’t give the BRAF inhibitor alone. You have to give it with at least a MEK inhibitor plus or minus an EGFR inhibitor.

John L. Marshall, MD: Again, if it’s an available drug, it may be 1 of those in which we muddy the overall survival.

Tanios Bekaii-Saab, MD: It is an international study, so the United States is going to muddy the water. Definitely.

John L. Marshall, MD: Yes, not everyone will have access.

Tanios Bekaii-Saab, MD: However, and as much as I don’t like to say that, those patients do so poorly that once they progress, it’s very unlikely that they’re going to cross over too much.

John L. Marshall, MD: And it’s not like this is some home-run, long tail trial. As you said, it’s about 2 to 4 months, right?

Paul R. Helft, MD: It may give you a couple months of breathing room.

Fortunato Ciardiello, MD, PhD: I know this is a reason why it’s attractive to use in these patients—FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan)/bevacizumab in the first-line setting—because you don’t know if you can do a second-line therapy in these patients. So, you try to put everything together, hoping that you have something that works.

Tanios Bekaii-Saab, MD: In the first-line setting, absolutely. Yes, these are the patients where I don’t even think twice about FOLFOXIRI/bevacizumab in the first-line setting. I don’t even think about it twice.

Transcript Edited for Clarity

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Transcript:

John L. Marshall, MD: Paul, talk a little bit about BRAF-mutant tumors. These are tumors that we think of as bad and tend to have a worse prognosis. Do we give EGFR therapies or not? Recent studies are trying to address this. Dr. Scott Kopetz’ SWOG S1406 study—talk a little bit about that.

Paul R. Helft, MD:BRAF-mutant tumors are sort of our arch enemy, in a way. They only account for about 8% or 9% of total colorectal cancers, but they’re obviously a driver mutation. They drive a really terrible biology because they tend to have a much worse prognosis. And, in a predictive sense, it is a negative predictive marker of response to therapy. They tend to not respond well to therapy.

Dr. Scott Kopetz of The MD Anderson Cancer Center, who’s a really terrific young clinician, investigator, and scientist, led SWOG S1406, which was a trial in patients who have BRAF mutations of irinotecan plus cetuximab with or without vemurafenib. Playing on this interest in whether or not we can inhibit the effects of the BRAF mutation in this population—because, clearly, as a single agent, this is not working at all in colorectal cancer, so hence the combination—there was indeed, in this abstract, a 2.5-month progression-free survival advantage. And, if the patients had not seen irinotecan, previously, there was almost a 6-month progression-free survival advantage in that trial.

John L. Marshall, MD: But the control arm of BRAF-mutated tumors with EGFR make it look like it did the work. So, for me, at least, this is practice changing because I don’t really want to give an EGFR therapy to a BRAF-mutated tumor without this combination. Do you agree?

Fortunato Ciardiello, MD, PhD: I agree.

John L. Marshall, MD: How do we get it? Is this one of those situations where you call up the company and ask for approval?

Paul R. Helft, MD: Or, I think, use the trial as a mechanism for getting United States insurance companies…

John L. Marshall, MD: The upcoming trial, the BEACON CRC study, I think?

Tanios Bekaii-Saab, MD: The BEACON CRC study, yes.

John L. Marshall, MD: But, that has a control arm, right?

Tanios Bekaii-Saab, MD: It has a control arm with FOLFIRI (folinic acid, fluorouracil, and irinotecan)/cetuximab. Unfortunately, you have to have that arm. But, like you said, at least in the United States, these agents are available. For patients where I didn’t have a trial, I’ve actually been able to get them. You wouldn’t give the BRAF inhibitor alone. You have to give it with at least a MEK inhibitor plus or minus an EGFR inhibitor.

John L. Marshall, MD: Again, if it’s an available drug, it may be 1 of those in which we muddy the overall survival.

Tanios Bekaii-Saab, MD: It is an international study, so the United States is going to muddy the water. Definitely.

John L. Marshall, MD: Yes, not everyone will have access.

Tanios Bekaii-Saab, MD: However, and as much as I don’t like to say that, those patients do so poorly that once they progress, it’s very unlikely that they’re going to cross over too much.

John L. Marshall, MD: And it’s not like this is some home-run, long tail trial. As you said, it’s about 2 to 4 months, right?

Paul R. Helft, MD: It may give you a couple months of breathing room.

Fortunato Ciardiello, MD, PhD: I know this is a reason why it’s attractive to use in these patients—FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan)/bevacizumab in the first-line setting—because you don’t know if you can do a second-line therapy in these patients. So, you try to put everything together, hoping that you have something that works.

Tanios Bekaii-Saab, MD: In the first-line setting, absolutely. Yes, these are the patients where I don’t even think twice about FOLFOXIRI/bevacizumab in the first-line setting. I don’t even think about it twice.